5-Amino or substituted amino 1,2,3-triazoles have been known as anticoccidiosis agents. As such the compounds and the preparations thereof were disclosed in the U.S. Pat. No. 4,590,201. These compounds have also been described and disclosed as useful in the treatment of psoriasis in copending U.S. patent application Ser. No. 087,494, filed Aug. 20, 1987, now U.S. Pat. No. 4,847,257 issued July 11, 1989.
Psoriasis is a chronic skin disease which is characterized by hyperproliferation of the epidermis as well as by focal accumulations of lymphocytic cells. Cell cycle estimates in psoriasis suggest that the average germinative psoriatic cell divides every 37 hours compared to 152 hours in normal skin, and the role of hyperproliferation in the production of lesions is evidenced by the fact that antiproliferitive agents such as methotrexate are presently used therapeutically for symptomatic treatment of the disease. Other chemotherapeutic agents which have been used experimentally with success in clearing lesions include similar antimetabolites which disrupt nucleotide metabolism and thereby inhibit proliferation such as mycophenolic acid or thioguanine. The importance of the inflammatory component of the disease and the involvement of the arachidonate cascade in psoriasis is suggested by the elevated levels of arachidonate metabolites found in psoriatic skin compared to normal skin. Some of these metabolites, such as LTB.sub.4 or 12-HETE, are potent chemoattractants capable of causing polymorphonuclear leukocyte invasion of the skin, whereas others such as prostaglandins D.sub.2, E.sub.2 and I.sub.2 cause erythema, vasodilation and edema. The ability of glucocorticoids to inhibit the release of arachidonate by regulating phospholipase A2 is presumably responsible for at least part of the therapeutic value of this class of antipsoriatic agents.
In our in vitro studies on antiproliferative agents, it became apparent that 5-amino-1,2,3-triazoles were topically active antiproliferative agents which also inhibited the production of a broad array of arachidonate metabolites. Therefore, it appeared that these compounds would be able to simultaneously inhibit both of the pathological states associated with the psoriasis. Rather than being the fortuitous appearance of two unrelated pharmacological activities, the compound apparently inhibits the primary agonist-generated signal responsible for either the production of eicosanoids or for the initiation of cell division.
Upon further testing by accepted in vivo models, we were able to demonstrate that these amino-1,2,3-triazole analogs were potentially effective in the treatment and management of psoriasis, inflammatory bowel syndrome, cutaneous leishmanilisis, and might also be effective in the treatment of certain types of cancer that involved the transportation of individual cells to other tissues from a metastasizing tumor.